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•TCS exposure induced increase in liver weight, but not body weight in mice.•TCS exposure induced accumulation of FFAs in mouse liver.•TCS induced GP remodeling, accumulation of Cer ...and TG in mouse liver.•Disorders in lipid metabolism imply the hepatotoxicity of TCS in mice.
Previous in vivo exposure studies focused mainly on nuclear receptors involved in hepatotoxicity of triclosan (TCS). As liver plays a vital role in metabolic processes, dysregulations in lipid metabolism have been identified as potential drivers of pathogenesis. Investigation of changes in lipid metabolism might widen our understanding of toxicological effects as well as the underlying mechanism occurring in the liver. In this study, we comprehensively assessed the effect of TCS exposure on hepatic lipid metabolism in mice. Our results showed that TCS induced significant changes in hepatic free fatty acid pool by upregulation of fatty acid uptake and de novo fatty acid synthesis. Besides, hepatic levels of lipids, including acyl carnitine (AcCa), ceramide (Cer), triacylglycerols (TG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) were also increased, together with upreguation of genes associated to TG synthesis, fatty acid oxidation and inflammation in TCS exposure group. These changes in lipid homeostasis could contribute to membrane instability, lipid accumulation, oxidative stress and inflammation. Our results suggested that TCS exposure could induce hepatic lipid metabolism disorders in mice, which would further contribute to the liver damage effects of TCS.
Residues of glyphosate (GLY) are widely detected in aquatic systems, raising potential environmental threats and public health concerns, but the mechanism underlying GLY-induced hepatotoxicity in ...fish has not been fully elucidated yet. This study was designed to explore the hepatotoxic mechanism using juvenile common carp exposed to GLY for 45 d, and plasma and liver samples were collected at 15 d, 30 d, and 45 d to analyze the assays. First, GLY-induced hepatic damage was confirmed by serum liver damage biomarker and hepatic histopathological analysis. Next, changes in oxidative stress biomarkers, gene expression levels of pro- and anti-inflammatory cytokines, and lipid metabolism-related parameters in collected samples were analyzed to clarify their roles in GLY-induced hepatic damage. Data showed that oxidative stress was an early event during GLY exposure, followed by hepatic inflammatory response. Lipid metabolism disorder was a late event during GLY exposure, as evidenced by overproduced hepatic free fatty acids, enhanced lipogenesis-related gene expression levels, reduced lipolysis-related gene expression levels, and resultant hepatic lipid accumulation. Collectively, these findings demonstrate that GLY induces hepatotoxicity in fish through involvement of oxidative stress, inflammatory response, and lipid metabolism disorder, which are intimately interrelated with each other during GLY exposure.
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•Sub-chronic glyphosate (GLY) exposure induces hepatic damage in fish.•Oxidative stress and resultant inflammatory response are involved in GLY-exposed fish.•GLY-induced inflammation contributes to hepatic lipid metabolism disorder in fish.•GLY-induced hepatotoxicity in fish is due to lipid metabolic disorders.
Subclinical ketosis (SCK) in dairy cows is often misdiagnosed because it lacks clinical signs and detection indicators. However, it is highly prevalent and may transform into clinical ketosis if not ...treated promptly. Due to the negative energy balance, a large amount of fat is mobilized, producing NEFA that exceeds the upper limit of liver processing, which in turn leads to the disturbance of liver lipid metabolism. The silent information regulator 1 (SIRT1) is closely related to hepatic lipid metabolism disorders. Exosomes as signal transmitters, also play a role in the circulatory system. We hypothesize that the circulating exosome-mediated adenosine 5′-monophosphate (AMP)-activated protein kinase alpha (AMPKα)–SIRT1 pathway regulates lipid metabolism disorders in SCK cows. We extracted the exosomes required for the experiment from the peripheral circulating blood of non-ketotic (NK) and SCK cows. We investigated the effect of circulating exosomes on the expression levels of mRNA and protein of the AMPKα–SIRT1 pathway in non-esterified fatty acid (NEFA)-induced dairy cow primary hepatocytes using in vitro cell experiments. The results showed that circulating exosomes increased the expression levels of Lipolysis-related genes and proteins (AMPKα, SIRT1, and PGC-1α) in hepatocytes treated with 1.2 mM NEFA, and inhibited the expression of lipid synthesis-related genes and protein (SREBP-1C). The regulation of exosomes on lipid metabolism disorders caused by 1.2 mM NEFA treatment showed the same trend as for SIRT1-overexpressing adenovirus. The added exosomes could regulate NEFA-induced lipid metabolism in hepatocytes by mediating the AMPKα–SIRT1 pathway, consistent with the effect of transfected SIRT1 adenovirus.
•Primary hepatocytes are treated with 40 μg/mL of plasma exosomes for 12 h showing maximum activity.•Exosomes can promote lipid oxidation and breakdown through the AMPK α -SIRT 1 pathway.•NK and SCK-derived exosomes can play similar roles in hepatic lipid metabolism as overexpressing adenovirus SIRT 1.•SCK-derived exosomes are more effective than NK-derived in alleviating hepatic lipid metabolism disorders in dairy cows.
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can ...negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.
Gentiopicroside (GPS) decreased progestin and adipoQ receptor 3 (PAQR3) expression by promoting DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Importantly, GPS bound directly to PAQR3 and spatially inhibited the combination between PAQR3 and P110α to restore PI3K/AKT signaling. Display omitted
Various microplastics (MPs) are found in the environment and organisms. MP residues in organisms can affect health; however, their impacts on metabolism in aquatic organisms remain unclear. In this ...study, zebrafish embryos were exposed to polyethylene MPs with sizes ranging from 1 to 4 μm at concentrations of 0, 10, 100, and 1000 μg/L for 7 days. Through qPCR technology, the results indicated that zebrafish exposed to polyethylene MPs exhibited significant change in microbes of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia, etc. Moreover, 16S RNA gene sequencing revealed that there was a significant difference in alpha diversity between the control and 1000 μg/L MP-treated groups. At the genus level, the abundance of Aeromonas, Shewanella, Microbacterium, Nevskia and Methyloversatilis have increased remarkably. Conversely, the abundance of Pseudomonas, Ralstonia and Stenotrophomonas were significant reduction after MPs exposure. In addition, the levels of TG (triglyceride), TCHO (total cholesterol), NEFA (nonesterified fatty acid), TBA (total bile acid), GLU (glucose) and pyruvic acid significantly changed in MP-treated larval zebrafish, indicating that their metabolism was disturbed by MPs. Transcriptional levels of glucose and lipid metabolism-related genes showed a decreasing trend. Furthermore, LC/MS-based nontargeted metabolomics analysis demonstrated that a total of 59 phospholipid-related substances exhibited significant changes in larval fish treated with 1000 μg/L MPs. The mRNA levels of phospholipid metabolism-related genes were also obviously changed. Pearson correlation analysis indicated that the abundance of Aeromonas, Shewanella and Chitinibacter bacteria showed a negative correlation with most phospholipids, while Nevskia, Parvibacter and Lysobacter showed a positive correlation with most phospholipids. Based on these results, it is suggested that 1–4 μm PE-MPs could impact the microbiome and metabolism of larval zebrafish. All of these results indicated that the health risk of MPs cannot be ignored.
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•Exposure of 1–4 μm PE-MPs caused microbiome dysbiosis in larval zebrafish.•PE-MPs decreased the mRNA expression level of glycolipid metabolism genes in larval zebrafish.•PE-MPs disrupted the metabolic profile of larval zebrafish.•The changed phospholipid metabolism was tightly related to microbiota change.
The present study observed that polyethylene microplastics exposure could change the composition of microbiome and metabolism in larval zebrafish.
Isobavachalcone (IBC) is a flavonoid component derived from Psoraleae Fructus that can increase skin pigmentation and treat vitiligo. However, IBC has been reported to be hepatotoxic. Current studies ...on IBC hepatotoxicity are mostly on normal organisms but lack studies on hepatotoxicity in patients. This study established the depigmented zebrafish model by using phenylthiourea (PTU) and investigated the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC and the underlying mechanism. Morphological, histological, and ultrastructural examination and RT-qPCR verification were used to evaluate the effects of IBC on the livers of zebrafish larvae. IBC significantly decreased liver volume, altered lipid metabolism, and induced pathological and ultrastructural changes in the livers of zebrafish with depigmentation compared with normal zebrafish. The RNA-sequencing and RT-qPCR results showed that the difference in hepatotoxicity between normal and depigmented zebrafish caused by IBC was closely related to the calcium signaling pathway, lipid decomposition and metabolism, and oxidative stress. This work delved into the mechanism of the enhanced IBC-induced hepatotoxicity in depigmented zebrafish and provided a new insight into the hepatotoxicity of IBC.
This experiment explored the effects of Lycium barbarum polysaccharides (LBP) on lipid metabolism of spotted sea bass Lateolabrax maculatus. Blank and experimental control diets with 100 and 150 g/kg ...lipid were designed, respectively, and three dosages of LBP (0.75, 1.00, 1.25 g/kg) were supplemented in the experimental control diet. A total 375 of spotted sea bass (19.33 ± 0.15) g were divided into 5 groups, and were given experimental diets for 56 days, respectively. Results showed fish were induced to lipid metabolism disorders with dietary 150 g/kg lipid intake, which manifested in reduced feeding, oxidative stress, elevated serum lipid, and more severe hepatic damage. Dietary LBP improved the lipid metabolism disorders of fish, as indicated by significant enhancements in weight gain, digestion, superoxide dismutase activity, and decreases in malonaldehyde content, and activity of alanine aminotransferase and aspartate aminotransferase. Accordingly, an improvement in the hepatic morphological and expression of lipid metabolism related genes, including FAS, PPAR-α, CPT1 and ATGL, was observed. Nevertheless, no significant variation in serum triglyceride and total cholesterol was observed. Overall, dietary LBP can improve the growth, digestion, antioxidant capacity, and liver health of spotted sea bass, thereby improving the lipid metabolism disorders induced by 150 g/kg dietary lipid intake.
Exposure of endocrine disrupting chemicals (EDCs) is closely related to induction of obesity, nonalcoholic fatty liver disease (NAFLD) and other lipid-metabolism diseases. Herein, we compared the ...effects of three EDCs exposure (triclosan, bisphenol A and fluorene-9-bisphenol) on lipid metabolism in zebrfish (Danio rerio). The differential lipid-metabolism disorders were analyzed in depth through RNA-Seq and qRT-PCR, as well as assessment of the relationship between lipid disorder and RNA methylation. Histopathological observation along with varying physiological and biochemical indexes all identified that triclosan and bisphenol A induced liver fat accumulation in acute and chronic exposure. RNA-Seq analysis showed that triclosan exposure disrupted multiple physiological processes including drug metabolism, sucrose metabolism, fat metabolism and bile secretion. The dysregulation of lipid-metabolism related genes indicated that liver steatosis in triclosan and BPA-exposed zebrafish resulted from increased fatty acid synthetase, and uptake and suppression of β-oxidation. Besides, the dysregulation of pro-inflammatory genes and endoplasmic reticulum stress showed that triclosan and bisphenol A exposure not only induced occurrence of NAFLD, but also promoted progression of hepatic inflammation. However, no significant effect on lipid metabolism was observed in fluorene-9-bisphenol-exposed treatment although the larval phenotypic malformation was found compared to the control group. Moreover, EDCs exposure led to decreased global m6A level and abnormal expression of m6A modulators in larvae. Especially, the expression of demethylase FTO (fat mass and obesity-associated protein) was significantly increased in triclosan-exposure treatment. These findings are conductive for us to deeply understand the underlying molecular mechanisms regarding the obesity and NAFLD from EDCs exposure.
•Triclosan and bisphenol A exposure results in lipid metabolism disorder in zebrafish.•TCS exposure increases lipogenesis and lipid transport, and inhibits lipid oxidation.•TCS exposure affect drug, fatty acid and sucrose metabolism pathways in zebrafish.•TCS and BPA induce the abnormal expression of ER and inflammation related genes.•Reduced global RNA m6A methylation upon exposure to three endocrine disruptors.
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•Spirulina platensis polysaccharides (SPLP) had significant hypolipidemic and hypoglycemic effects in HFD-fed rats.•SPLP intervention modulate the hepatic steatosis and mRNA ...expressions involved in lipid and carbohydrate metabolism.•SPLP altered the relative abundance of cecal short-chain fatty acids.•SPLP significantly modulated the intestinal microbiota dysbiosis.
This study aimed to evaluate the possibility that Spirulina platensis crude polysaccharides may ameliorate the lipid and carbohydrate metabolism disorder, including obesity, hyperlipidemia, hyperglycemia, hepatic steatosis, and gut dysbiosis. The results showed Spirulina platensis crude polysaccharides could improve body weight, serum/liver lipid and carbohydrate indexes, and liver antioxidant parameters in high-sucrose and high-fat diet (HFD)-fed rats, which were accompanied by regulated liver mRNA expressions involved in lipid and carbohydrate metabolism disorder. In addition, SPLP intervention significantly decreased cecal level of propionic acid in HFD-fed rats. Notably, the SPLP could alter the relative abundance of Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria at phylum levels. Based on Spearman's rank correlation coefficient, serum/liver lipid and carbohydrate profiles were found significantly positively correlated with genera Romboutsia, Allobaculum, Blautia, Phascolarctobacterium, Bifidobacterium, Coprococcus, Turicibacter, Erysipelotrichaceae_unclassified, Olsenella, Escherichia/Shigella, Coprobacillus, Lachnospiracea incertae, and Lactobacillus, but strongly negatively correlated with genera Atopostipes, Flavonifractor, Porphyromonadaceae_unclassified, Barnesiella, Oscillibacter, Paraprevotella, Jeotgalicoccus, Corynebacterium, Alloprevotella and Bacteroides. It was concluded that oral administration of SPLP could remarkably ameliorate the lipid and carbohydrate metabolism disorder and significantly modulate the intestinal microbiota in HFD-fed rats.
Microplastics are major pollutants in marine environment and may have health effects on aquatic organisms. In this study, we used two sizes (5 and 50 μm diameter) of fluorescent and virgin ...polystyrene microplastics to analyze the adverse effects on larval zebrafish. In our study, we evaluated the effects on larval zebrafish after exposure to 100 and 1000 μg/L of two sizes of polystyrene microplastics for 7 days. Our results show that polystyrene microplastics could cause alterations in the microbiome at the phylum and genus levels in larval zebrafish, including changes in abundance and diversity of the microbiome. In addition, metabolomic analysis suggested that exposure to polystyrene microplastics induced alterations of metabolic profiles in larval zebrafish, and differential metabolites were involved in energy metabolism, glycolipid metabolism, inflammatory response, neurotoxic response, nucleic acid metabolism, oxidative stress. Polystyrene microplastics also significantly decreased the activities of catalase and the content of glutathione. In addition, the results of gene transcription analysis showed that exposure to polystyrene microplastics induced changes in glycolysis-related genes and lipid metabolism-related genes, confirming that polystyrene microplastics disturbed glycolipid and energy metabolism. Taken together, the results obtained in the present study indicated that the potential effects of environmental microplastics on aquatic organisms should not be ignored.
•Polystyrene MPs induced gut microbiota dysbiosis in larval zebrafish.•Polystyrene MPs disturbed the transcription of genes related to glucose and lipid metabolism in larval zebrafish.•Polystyrene MPs caused metabolism disorder in larval zebrafish.
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